Dysregulation of the hypothalamic-pituitary-adrenal axis (HPA), which controls the endocrine stress response, has been implicated in the pathogenesis of stress-related disorders including depression and anxiety. It is believed that at least part of the dysfunction is related to a lack of glucocorticoid-mediated negative feedback to the hypothalamus. It has been hypothesized that glucocorticoid receptors (GRs) within the hippocampus (HPC) are important mediators of this inhibition. In order to investigate this hypothesis we will take advantage of recent advances in transgenic technology. We have generated mice with a conditional knockout of the GR in area CA1 of the HPC. In addition, we are in the process of generating mice with inducible expression of GRs in the HPC. Analysis of these two lines of mice will allow us to discretely address the role of GRs within the HPC in regulation of the HPA axis. We will examine these mice for changes in basal and/or stress-induced activation of the HPA axis. These mice will also be analyzed for changes in stress/depression related behaviors. Decreased hippocampal GR has been associated with a number of animal models of depression, while increased hippocampal GR is correlated with a decreased susceptibility to depression. We will therefore examine how changes in GR expression in the HPC influence depression related behaviors including anxiety, despair, anhedonia, and learning. We will further examine whether these mutations influence susceptibility to two established models of depression: chronic mild stress and social defeat.